Title of Invention

"PROCESS FOR THE PREPARATION OF 2'-FLUORO-5-METHYL-B-L-ARABINO-FURANOSYLURIDINE"

Abstract

A process for preparing 2'-fluoro-5-methyl-p-L-arabino-furaranosyluridine (L-FMAU) of formula (I) from L-arabinose of formula (4) comprising the following steps : (i) inverting the C9 hydroxyl group of the compound of formula (4) from an arabinose configuration (up) to a ribose (down) configuration via an oxidation and reduction reaction at C2 center, wherein R is benzoyl, aryl or aralkyl to obtain a ribopyranose intermediate; (ii) converting the ribopyranose intermediate to ribo— furanose intermediate under acidic conditions wherein described; (iii) displacing the protected hydroxyl group at C2 (ribo configuration) of the ribofuranose intermediate via fluorination reaction carried out in a condition as wherein described to provide a 2'-fluoro substituent in the arabinose configuration which further provides the C1 halogenated 2'-fluoroarabinofuranose intermediate; (iV) condensing the said C. halogenated 2'-fluoroarabinofuranose intermediate with a base to provide a precursor of a compound of formula (l)

Full Text

PROCESS FOR THE PREPARATION OF 2'-FLUORO-5-METHYL- ß -L-ARABINO- FURANOSYTURIDINE TECHNICAL FIELD The present invention relates to an improved process for preparing 2'-fluoro-5-methyl-;?-L-arabinofuranosyluridine(generic name: Levovir, hereinafter referred to as "L-FMAU") represented by formula (1), which shows anti-viral activity, especially potent anti-viral activity against hepatitis B-virus(HBV) and Epstein-Bar virus(EBV): (Formula Removed) BACKGROUND ART Various nucleoside compounds, including L-FMAU of formula (1) have been disclosed (see, for example, International PubUcation No. WO 95/20595): (Formula Removed) in which R' represents purine or pyrimidine base; and R" represents hydrogen, acyl, alkyl, monophosphate, diphosphate or triphosphate. Nucleoside compounds of formula (2) exhibit anti-viral activity against BDBV and EBV. Among these nucleoside compounds, L-FMAU shows particularly potent anti-viral activity against HBV and EBV with very- low cytotoxicity and is, therefore, preferred as an anti-viral agent. Nucleoside compounds of formula (2), including L-FMAU, are useful in the prevention and treatment of HBV infections and related conditions, such as anti-HBV antibody positive and HBV-positive conditions, chronic hver inflammation caused by HBV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue. In addition, they can also be used for the treatment of EBV-associated disorders. According to the method disclosed in International Publication No. WO 95/20595, L-FMAU of formula (1) may be prepared using L-xylose of formula (3) as a starting material : (Formula Removed) L-xylose of formula (3) cannot be obtained from natural substances and must therefore be produced by synthetic methods. When L-x>iose is used as the starting material, the production cost of L-FMAU is therefore very high. OBJECT OF INVENTION It has been discovered that L-FMAU can be economically prepared from L-arabinose, which is present in many natural substances and, thus, is an inexpensive starting material, thereby completing the present invention. In accordance with the present invention there is disclosed a process for preparing 2'-fluoro-5- methyl-(3-L-arabino-furaranosyluridine (L-FMAU) of formula (1) (Formula Removed) from L-arabinose of formula (4) (Formula Removed) comprising the following steps: (i). inverting the CT hydroxyl group of the compound of formula (4) from an arabinose configuration (up) to a ribose (down) configuration via an oxidation and reduction reaction at C2 center, wherein R is benzoyl, aryl or aralkyl to obtain a ribopyranose intermediate; (ii). converting the ribopyranose intermediate to ribofuranose intermediate under acidic conditions as herein described; (iii). displacing the protected hydroxy! group at C2 (ribo configuration) of the ribofuranose intermediate via fluorination reaction carried out in a condition as herein described to provide a 2'-fluoro substituent in the arabinose configuration which further provides the Ci halogenated 2'-tluoroarabinofuranose intermediate ; (iv). condensing the said Ci halogenated 2'-fluoroarabinofuranose intermediate with a base to provide a precursor of a compound of formula (1). SUMMARY OF THE INVENTION An improved process for preparing 2'-tluoro-5-methyl-P-L-arabino-furanosyluridihe (L-FMAU) is disclosed which uses L-arabinose as the starting material. BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a schematic diagram of one method for the production of L-FMAU according to the disclosed process. Figure 1: (Figure Removed) BRIEF DESCRIPTION OF THE INVENTION The term alkyl, as used herein, unless otherwise specified, refers to a saturated straight, branched, or cyclic, primary, secondaiy, or tertiary hydrocarbon of Ci to Cio and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The alkyl group can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the eu't, for example, as taught in Greene, et al., "Protective Groups in Organic Synthesis," John Whiley and Sons, Second Edition, 1991. The term lower alkyl, as used herein, and unless otherwise specified, refers to a Ci to C4 saturated straight or branched alkyl group. The term aryl, as used herein, and unless otherwise specified, refers to phenyl, biphenyl, or naphtyl, and preferably phenyl. The aryl group can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those sldlled in the art, for example, as taught in Greene, et al., "Protective Groups in Organic Synthesis," John Wiley and Sons, Second Edition, 1991. The term aralkyl or arylalkyl refers to an aryl group with an alkyl substituent. The term acyl refers to moiety of the formula -C(0)R , wherein R^ is alkyl; alkyoxyalkyl including methoxymethyl; arylalkyl including benzyl; aryloxyall\;yl such as phenoxymethyl; aryl including phenyl optionally substituted with halogen, Ci to C4 alkyl or Ci to C4 alkoxy. According to the present invention, the desired compound, L-FMAU, of formula (1) can be economically prepared from the starting material of formula (4) by a process that utilizes the reaction set out in Figure 1, wherein: a) the starting material, L-arabinose of formula (4), is reacted with a compound of formula (18) to obtain a compound of formula (5); b) the compound of formula (5) is condensed with a compound of formula (19) to obtain the compound of formula (6), which is oxidized to obtain the compound of formula (7), which is then, reduced to obtain the compound of formula (8); c) the compound of formula (8) is treated with an acid to obtain the compound of formula (9), which is treated with the compound of formula (18) in the presence of an acid to obtain the compound of formula (10), which is reacted with an acyl-chloride such as benzoyl chloride to obtain the compound of formula (11), which is then reacted with an acid, for example, acetic acid and acetic anhydride in the presence of sulfuric acid to obtain the compound of formula (12); d) the compound of formula (12) is converted into the compound of formula (13); e) the compound of formula (13) is reacted with an agent for introducing a reactive leaving group to obtain the compound of formula (14); f) the compound of formula (14) is fluorinated to obtain the compound of formula (15), which is subjected to halogenation to obtain the compound of formula (16), which is then condensed with a thymine base to obtain the compound of formula (17); and g) the compound of formula (17) is treated with ammonia in methanol to produce the desired L-FMAU of fonnula (1). In the above reaction scheme, R represents a hydroxy-protecting group such as alkyl, aryl, halogenoalkyl, aralkyl, etc., Ri and R2 independently of one another represent hydrogen, alkyl or aryl, L represents a reactive leaving group such as imidazolylsulfonyl, toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, etc., and Hal represents a halogen atom such as chloro or bromo. The process of the present invention is explained in more detail below. As illustrated in Figure 1, by reacting the starting material, L-arabinose of formula (4), with an alcohol of formula (18), for example, benzyl alcohol, in the presence of hydrogen chloride gas, the 1-hydroxy group of L-arabinose is protected to produce the compound of formula (5). In reaction b), the compound of formula (5) prepared in the reaction a) is condensed with a propane derivative of formula (19), for example, 2,2-dimethoxypropane, to produce the compound of formula (6). The compound of formula (6) is oxidized to produce the compound of formula (7), which is subsequently reduced to produce the compound of formula (8). In this reaction, oxidizing agents which can preferably be used include aqueous chromic acid (CrOa), sodium dichromate (Na2Cr07), pyridinium chlorochromate (POC), pyridinium dichromate (PDC), potassium permanganate (KMn04), lead tetraacetate/pyridine, oxygen over platinum/ carbon catalyst, Ru04, Ru04/NaI04, dimethylsulfoxide/dicyclohexylcarbo-diimide (DMSO/DCC) and a proton donor, silver carbonate, triphenyl bismuth carbonate, Oppenauer oxidation (aluminum alkoxides in acetone), chlorine dioxide- (CIO2), dimethylsulfoxide/oxalyl chloride (DMS0/(C0C1)2), dimethylsulfoxide/sulfuryl chloride (DMSO/SO2CI2), dimethylsulfoxide/ thionyl chloride (DMSO/SOCI2), dimethylsulfoxide/toluenesulfonyl chloride (DMSO/TsCl), dimethylsulfoxide/trifluoroacetic anhydride (DMSO/ (CF3CO)20), dimethylsulfoxide/acetic anhydride (DMSO/AC2O), etc. Among them, pyridinium dichromate in the presence of a solvent such as dichloromethane is particularly preferred. Reducing agents which can preferably be used include sodium borohydride (NaBIii), diisobutyl-aluminum hydride (DEBAL-H), hthium borohydride (LiBIli), sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), hthium aluminum hydride (LiAlH4), potassium borohydride (KBH4), Raney nickel, rhodium/ hydrogen (H2), palladium/hydrogen, platinum/hydrogen, rubidium/hydrogen. rubidium-silica/hydrogen, etc. Among them, sodium borohydride (NaBILi) is particularly preferred. In reaction c), the compound of formula (8) is treated with an acid such as trifluoroacetic acid to remove the hydroxy-protecting group of the compoundO) and thereby produce the compound of formula (9), which is then treated with the compound of formula (18) in the presence of an acid, for example, methanol in the presence of hydrochloric acid to produce the compound of formula (10), which has a ribofuranose structure. The compound of formula (10) is then reacted with an acylchloride such as benzoyl chloride in the presence of a base to protect all the hydroxy groups of the compound of formula (10) with benzoyl groups, thereby producing the compound of formula (11). The compound of formula (11) is then treated with an acid such as acetic acid and anhydrous acetic acid in the presence of sulfuric acid to produce the compound of formula (12). The series of reaction steps for preparing the compound of formula (12) from the compound of formula (8) can preferably be practiced consecutively, without isolation of any intermediate. In reaction d), the compound of formula (12) produced in reaction c) is treated with hydrogen chloride in a solvent such as dichloromethane, cyclohexane, chloroform, etc., and then treated with water in a solvent such as acetonitrile to produce the compound of formula (13). In this reaction, the reaction by-product 1-hydroxy-isomer must be removed by treating with an ether such as dibutyl ether, diethyl ether, etc. In reaction e), the compound of formula (13) is reacted with an agent for introducing a suitable reactive leaving group, for example, sulfuryl chloride and imidazole, to produce the compound of formula (14). This reaction can be carried out in the presence of a solvent such as dimethylformamide, dichloromethane, etc. In reaction f), the compound of formula (14) produced in reaction e) is fluorinated in the presence of a solvent such as ethyl acetate, thereby substituting the reactive leaving group with fluorine to produce the compound of formula (15). In this reaction, the preferred fluori- nating agent includes potassium hydrogen fluoride (PCHF2)/hydrofluoric acid/pyridine or hydrofluoric acid/amine such as triethylamine. The resulting compound of formula (15) is then halogenated, for example, with hydrobromic acid or hydrochloric acid, in the presence of acetic acid to produce the compound of formula (16). The compound of formula (16) is then reacted with thymine base in the presence of hexamethyl-disilazane and ammonium sulfate to produce the compound of formula (17). This reaction can preferably be carried out in the presence of a solvent, for example, chloroform, dichloromethane, 1,2-dichloroethane, acetonitrile, etc. In reaction g), the compound of formula (17) produced in reaction f) is treated with ammonia in the presence of a solvent to remove the benzoyl group, the hydroxy-protecting group, from rhe compound of formula (17), thereby producing the desired compound L-FMAU. Although various aspects of the present invention are illustrated by the following examples, the present invention is not in any manner limited by these examples. Other reactants can be used as known to those of ordinary sldll, which perform substantially the same function. In the examples, the number of the compound in parentheses corresponds to the number in the reaction scheme A. Example 1 : Preparation of l-Q-benzvI-/g-L-arabinoside (5) Benzyl alcohol lOOOm^ was saturated with hydrogen chloride for 40 minutes at 0°C, 200g(1.33 mole) of L-arabinose was added and the resulting mixture was stirred at room temperature for 10 hours, during which a quantity of the compound (5) precipitated. To induce additional precipitation, 1.5 £ of ethyl acetate was slowly added while the mixture was stirred. The resulting solid product was filtered, washed with ethyl acetate and then dried in air to obtain 300g (Yield : 94%) of the title compound (5) in the form of a white solid. m.p. : 170-17ir H NMR (ppm) : 3.46(q, IH, J=2.87, 11.8), 3.63-3.73(m, 4H), 4.45(d, IH, J=12.8), 4.76(d, IH, J=12.32), 7.29-7.38 (m, 5H) Example 2 : Preparation of l-0-benzvl-3.4-0-isopropvlidene- B -L-riboside (8) A mixture of 200g(0.83 mole) of 1-0-benzyl-/9-L-arabinoside (5), 240i!}£(1.95 mole) of 2,2-dimethoxypropane and 4g(0.02 mole) of p-TsOH • H2O in 2000m£ of acetone was stirred at room temperature for 2 hours. The reaction mixture thereby obtained was neutralized with triethylamine and evaporated under reduced pressure to obtain the compound (6) in the form of a yellowish syrup, which was used for the next reaction without further purification. To a mixture of the compound (6) and 240g(0.63 mole) of pyridinium dichromate in 2000m£ of dichloromethane was added 240m£(2.54 mole) of acetic anhydride at 0°C and the mixture thereby obtained was then refluxed until the starting material disappeared (ca. 4 hours). At this time, the system was vented. The solvent was removed under reduced pressure until the mixture occupied one-third of its initial volume and the residue was poured into 1500m£ of ethyl acetate with vigorous stirring accomplished using a mechanical stirrer. The mixture thus obtained was filtered through a celite pad and the filter cake was thoroughly washed with ethyl acetate. The blackish combined filtrate was filtered through a siUca gel (2-20 micron) column (20cm height, 10cm diameter). The silica gel was washed with ethyl acetate until the compound (7) was no longer detected by TLC. The clear combined filtrate thereby obtained was evaporated to yield the compound (7) in the form of a syrup, which was coevaporated twice with toluene. The purified syrup (7) thus obtained was dissolved in 2000m£ of methanol and cooled to -20°C. 40g(1.06 mole) of NaBEU pellets were very slowly added to the resulting solution over 3 hours at -20°C. After completion of the reaction, the solution was neutralized with acetic acid, evaporated under reduced pressure to obtain a white solid residue. The residue was partitioned between lOOOM of ethyl acetate and 200m£ of water. The aqueous layer was extracted with 100m£ of ethyl acetate. The combined organic layer was washed with 200m£ of brine, dried over MgS04 and then evaporated to yield a white solid, which was recrystallized from 700m£ of hot hexane to yield 123g (Yield : 53% from the compound (5)) of the compound (8) in the form of a white crystal. m.p. : 79-80°C [a]% = +143° (c 0.7, ethanol) H NMR (ppm) : 1.37(s, 3H), 1.55(s, 3H), 2.37(d, IH, J=6.45), 3.71-3.76 (m, 2H), 3.86(q, IH, J=3.44 and 12.89), 4.27-4.30(m, IH), 4.49-4.52(m, IH), 4.56(d, IH, J=11.8), 4.83(d, IH, J=11.8), 4.86(d, IH, J=5.40), 7.26-7.36(m, 5H) Example 3 ■ Preparation of l-0-acetvl-2.3.5-tri-0-benzovl-^-L-ribofuranose (12) 201g(0.717 mole) of the compound (8) dissolved in 1000m£ of 4% trifluoroacetic acid(CF3C00H) was refluxed until the starting material (ca. 1 hour) and the intermediate (1-O-benzyl derivative) had disappeared (ca. 4-8 hours). The reaction mixture was cooled to room temperature and washed with dichloromethane (4X500iii£) to remove benzyl alcohol. The aqueous layer thereby obtained was evaporated in vacuo and coevaporated with toluene (2x200m£) to yield the compound (9) in the form of a yellowish syrup, which was completely dried tmder high vacuum to remove a trace amount of water. The compound (9) was dissolved in 2000in£ of methanol and 15.8g(0.43 mole) of HCl (gas) was bubbled into the mixture at room temperature. The mixture thereby obtained was stirred at room temperature for 2 hours, neutralized with 183m£ of pyridine and concentrated in vacuo at 30-35°C to give a yellowish syrup, which was in turn coevaporated with pyridine to yield the compound (10) in the form of a yellowish synrup. The compound (10) was dissolved in 800in£ of pyridine and 212ni£ of benzoyl chloride was added dropwise to the mixture at 0°C. The mixture was stirred at room tem.perature for 8 hours. After the reaction had gone almost to completion, the mixture was heated at 45 "C for 1.5 hour. The mixture was cooled to room temperature and ice was added to remove the remaining benzoyl chloride. Pyridine was evaporated from the mixture at 35-40 °C until the mixture occupied half of its initial volume. The residue was dissolved in 1500m£ of ethyl acetate, which was washed in succession with 500m£ of cold water, 576ni£ of cold 3N H2SO4, 500m£ of aqueous sodium bicarbonate (x2), and 500m.2 of brine, in that order. The organic layer was dried over MgS04 and activated carbon, filtered through a silica gel (2-20/^) pad and evaporated to obtain the compound (11) in the form of a yellowish syrup. To a mixture of the compound (11) dissolved in 144m£(2.52 mole) of acetic acid and 334m£(3.54 mole) of acetic anhydride, 48m£(0.9 mole) of C-H2SO4 was slowly added dropwise at 0°C, during which crystallization occurred. The mixture was brought to room temperature and kept in a refrigerator overnight. The mixture was poured into 700m£ of an ice-water mixture, filtered and the filter cal cold water. The solid was dissolved in 2000m^ of ethyl acetate, which was washed in succession with 500m£ of water, 500m£ of saturated sodium bicarbonate and 500m£ of brine. The organic layer was dried over MgS04 and activated carbon and the resulting mixtrue was filtered through a silica gel (2-20/i) pad. The solvent was removed and the residue was recrystalHzed from methanol to obtain 144.7g (Yield : 40% from the compound (8)) of the compound (12) in the form of a white solid. m.p. : 124-125 °C [α]D = -22.1° (c 1, pyridine) H NMR(CDCl3) S (ppm) : 8.90-7.32(m, 15H, Ar-H), 6.43(s, IH, H-1), 5.91(dd, IH, H-3, J=4), 5.79(d, IH, H-2, J=8), 4.81-4.76(m, 2H, H-4 and H-5), 4.54-4.49(m, IH, H-5), 2.00(s, 3H, CH3COO) F.Yample 4 : Preparation of 1.3,5-tri-O-benzovl-g-L-ribofuranose 1131 HCl (gas) was bubbled for 1.5 hours into a solution of 50g(99.16 mmole) of the compound (12) dissolved in 460ni£ of anhydrous dichloromethane and 7.5m^ of acetyl chloride at 0°C. The resulting solution was kept in a refrigerator for 12 hours and then evaporated in vacuo. The residue was coevaporated with toluene (3xi50itt£) at 45°C and redissolved in 105m£ of acetonitrile. To this solution, 13m£ of water was added drop wise at 0°C. A white solid began to precipitate from the mixture after 30 minutes, after which the mixture was kept in a refrigerator for 2 hours to induce additional precipitation. After filtration of the resulting solid, the filter calce was carefully washed with cold diethylether to remove the reaction by-product 1-hydroxy-isomer, which is indistinguishable by TLC from the compound (13). The white solid thereby obtained was dissolved in ethyl acetate. The solution was washed with saturated sodium bicarbonate to remove the remaining HCl, dried over MgSO.i and filtered. The solvent was removed from the filtrate to obtain 29.2g (Yield : 63.7%) of the compound (13) in the form of a wliite solid. m.p. : 137-139 °C [g]'°D = -82.01°. (c 1.5, CHCb) H NIR(CDCl3) S (ppm) : 7.31, 8.19(m, 15H, Ar-H), 6.69(d, J=4.6Hz, IH, H-1), 5.59(dd, J=6.7, 1.8Hz, IH, H-3), 4.64, 4.80(m, 4H, H-2, H-4 and H-5), 2.30(br s, D2O exchangable, OH) F.yample 5 : Preparation of 1.3.5-tri-0-benzovl-2-0-imidazolvl-sulfonvl-g-L-ribofuranose (14) 107.0g(0.232 mole) of the compound (13) was dissolved in 1070m^ of dicliloromethane and 214m^ of dimethylformamide, to which 62.5g(37.2 mi, 0.463 mole) of stdfuryl chloride was added dropwise at a low temperature (-10 to -7813). The resulting solution was stirred at room temperature for 3 hours and then cooled in an ice-bath. The solution was stirred while 157.8g(2.32 mole) of imidazole was added portionwise at the rate keeping the temperature of reaction mixture under 5°C. The resulting mixture was stirred at room temperature for 20 hours, after which 400nv£ of ice-water was added. The aqueous layer was extracted three times with 100m£ of dichloromethane (SxlOOnve). The combined organic solution was washed with 200M of brine and dried over MgS04. The solvent was removed under reduced pressure and dimethylformamide was removed under high vaccum. The syrupy residue was coevaporated with 100m£ of 2-propanol under reduced pressure to obtain a white soUd product (14), which was used for the next reaction without further purification. Example 6 : Preparation of l-(3.5-di-0-benzovl-2-fluoro-/?-L-arabinofuranosvDthymine (17) A mixture of the imidazolate (14) obtained from Example 5, 224.lg( 1.39 mole) of triethyIamine-3HF and 824[n£ of ethyl acetate was heated at 80°C for 3 hours, 70.3g(92.5iii£, 0.696 mole) of triethylamine was slowly added thereto and the mixture thereby obtained was stirred for one additional hour at the same temperature, after which the mixture was cooled to room temperature. The resulting solution was poured into ice-water containing NaHCOs to neutralize it to pH 7. The aqueous layer was extracted three times with lOOm^ of ethyl acetate (3xi00m£). The combined organic solution was washed with brine and dried over Na2S04. The solvent was removed and the residue was redissolved in 300n]g of dichloromethane, filtered through a silica gel pad and washed with dichloromethane. The solvent was removed to obtain 101.Og of crude 2-fluoro-sugar product (15), which was redissolved in 150m£ of dichloromethane. 195.9m£(88.2g, 1.09 mole) of hydrobromic acid/acetic acid(45% w/v) was added to the solution at 0°C and then stirred at room temperature for 15 hours. The resulting solution was evaporated to dryness under reduced pressure to give a syrup, which was coevaporated with toluene (3xi00m£) to obtan the sugar bromide (16) in the form of a semisolid, which was then redissolved in 200[n£ of chloroform for the condensation reaction described below. A mixture of 55.44g(0.44 mole) of thymine, 5g of ammonium sulfate{(NH4)2S04) and 212.5g(278.9Di£, 1.32 mole) of hexamethyldisilazane in 1900tii£ of chloroform was refluxed for 24 hours to give a nearly clear solution. A solution of sugar bromide (16) in chlorofonn was added and the resulting mixture was refluxed for additional 24 hours and then cooled to room temperature. 200ni£ of water was added to the reaction mixture, which was stirred at room temperature for 30 minutes and then filtered. The organic layer was separated, dried over Na2S04, and filtered through a celite pad, which was then washed with ethyl acetate. The combined organic solution was evaporated to give a solid which was recrystallized from 100iii£ of ethanol to obtain 78.Og (Yield : 69.5% from the alcohol compound (13)) of 3,5-0-dibenzoyl L-FIVIAU (17) in the form of a crystal. m.p. : 118-120t laf% - +22.40° (c 0.31, CHCI3) UV (MeOH) Aju^^ 264.0nm 'H NMR(CDCy d (ppm) : 8.55(s, NH), 7.37, 8.12(m, Ar), 6.35(dd, JF-H = 22.4Hz, H-1'), 5.64(dd, JF-H=20.4HZ, H-3'), 5.32(dd, JF-H=50.2HZ, H-2'), 4.82(m, H-5), 4.50(m, H-4'), 1.76(s, CH3) Example 7 : Preparation of 2'-fluoro-5-methvl-j9-L-arabinofura-nosyluridine (1) NH3 gas was bubbled for 2-3 hours into a suspension of 83.0g(0.18 mole) of the compound (17) in lOOOm^ of methanol to obtain a clear solution, which was then stirred at room temperature for an additional 48 hours. The solvent was removed under reduced pressure and the residue was triturated with diethyl ether. The resulting solid was collected by filtration, redissolved in 500nv£ of methanol and twice decolorized with charcoal. Methanol was removed and the resulting solid was refluxed with 200m£ of acetonitrile for 2 hours. The resulting mixture was cooled in refrigerator for 15 hours and then filtered to obtain 35.6g (Yield : 77.35%) of a white solid. The mother hquor was concentrated to dryness and purified by silica gel column chromatography (1-10% methanol in chloroform) to obtain a white solid, which was refluxed with 20m£ of acetonitrile to obtain 4.98g (Yield : 10.8%) of the second crop of the product. Total yield was raised to 88.2% (40.58g). m.p. : 185-187 °C [a]%= -112.06° (c 0.23, methanol) UV (H2O) max 265.0 ie 9695)(pH 2), 265.5 ie 9647)(pH 7), 265.5nm is 7153)(pH 11) H NMR(DMSO-dG) d (ppm) : 11.45(s, NH), 7.59(s, H-6), 6.10(dd, JF-H= 15.4Hz, H-1'), 5.88(d, 3'-0H), 5.12(t, 5'-0H), 5.04(dt, JF-H=52.8HZ, H-2'), 4.22 (dq, JF-H=18.4HZ, H-3'), 3.76(m, H-4'), 3.63(m, H-5'), 1.78(s, CH3) The invention has been described with reference to its preferred embodiments. Variations and modifications of the invention will be obvious to those sldlled in the art from the foregoing detailed description of the invention. It is intended that all of these variations and modifications be included within the scope of the appended claims. WE CLAIM 1. A process for preparing 2'-fluoro-5-methyl-ß-L-arabino-furaranosyluridine (L-FMAU) of formula (1) (Formula Removed) from L-arabinose of formula (4) (Formula Removed) comprising the following steps: (i). inverting the C2 hydroxyl group of the compound of formula (4) from an arabinose configuration (up) to a ribose (down) configuration via an oxidation and reduction reaction at C2 center, wherein R is benzoyl, aryl or aralkyl to obtain a ribopyranose intermediate; (ii). converting the ribopyranose intermediate to ribofuranose intermediate under acidic conditions as herein described', (iii). displacing the protected hydroxyl group at C2 (ribo configuration) of the ribofuranose intermediate via fluorination reaction carried out in a condition as herein described to provide a 2'-fluoro substituent in the arabinose configuration which further provides the C1 halogenated 2'-fluoroarabinofuranose intermediate ;' (iv). condensing the said C1 halogenated 2'-fluoroarabinofuranose intermediate with a base to provide a precursor of a compound of formula (1). 2. A process for preparing 2'-fluoro-5-methyl-ß-L-arabino-furaranosyluridine (L-FMAU) substantially as herein described with reference to the foregoing description and the accompanying examples.

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